Breast Cancer CTCs Can Flip Between HER2 Negativity and Positivity

Breast cancer tumors that are human epidermal growth factor receptor 2 (HER2)-negative can spontaneously flip, with populations of circulating HER2-positive cells, according to a new study. The finding carries implications for treatment of patients with tumors of varying molecular characteristics.

Previous research has shown that circulating tumor cells (CTCs) in women with advanced estrogen receptor (ER)-positive/HER2-negative breast cancer can acquire a subpopulation of HER2-positive cells after therapy. In the new study, researchers co-led by Shyamala Maheswaran, PhD, of Massachusetts General Hospital Cancer Center in Boston, confirmed this acquired HER2 positivity and also looked into how changes occur in the molecular characteristics of the tumor. The results were published in Nature.

In a cohort of 19 women with ER-positive/HER2-negative disease, 16 (84%) had HER2-positive CTCs after multiple courses of therapy. The fraction of HER2-positive cells increased with disease progression.

The researchers found that there were discrete HER2-negative and HER2-positive CTC subpopulations. The HER2-negative cells showed activation of the Notch pathway and were sensitive to Notch inhibition; the HER2-positive cells, meanwhile, are more proliferative but “not addicted to HER2,” suggesting activation of multiple pathways.

The differing proliferation rates of these two types of CTCs suggested to the investigators that they might “interconvert” between positivity and negativity. After 4 weeks in cell culture, both types acquired the other type, though HER2-positive cells generated HER2-negative cells at a lower rate. In single cell–derived CTC colonies, both HER2-negative and HER2-positive cells generated the opposite in the five- to nine-cell stage of doubling, though again the HER2-negative cells were generated more slowly.

Next, a mouse study was conducted to determine if targeting both these molecular states could benefit patients. The combination of paclitaxel and either of two gamma secretase inhibitors (which inhibit the Notch pathway) significantly delayed the onset of tumor recurrence compared with paclitaxel alone; the Notch inhibitors had no effect on tumor growth when administered alone.

“The ability of these two populations of tumor cells to convert back and forth highlights the importance of treating tumors with drugs that would simultaneously target both populations,” Maheswaran said in a press release. “Now we need to investigate the mechanisms responsible for this interconversion.”